In humans, a common risk factor for the development of invasive breast cancer is dense breast tissue, detected by mammography. This dense tissue is associated with increased stromal collagen, increased epithelial cells, and decreased fatty tissue. Recent studies in transgenic mice indicate that increased collagen density in breast stromal tissue plays a causative role in promoting both the formation and invasiveness of breast tumors. Additional studies implicate tissue rigidity downstream of extracellular matrix (ECM) deposition and/or cross linking in promoting aggressive, invasive cellular phenotypes. Conversely, basement membrane ECM proteins that underlie normal and carcinoma in situ epithelial cells are thought to inhibit tumor progression. Because of the complexity of extracellular matrix-tumor cell interactions, it is difficult to fully isolate and understand the various effects of extracellular matrix on tumor progression using traditional biological approaches. We therefore propose to use an interdisciplinary approach in which we develop a 3-dimensional cell-based multiscale mathematical model of ECM-breast cancer interactions. Using this model, we will perform in silico experiments to test the overall hypothesis that ECM rigidity and stromal collagen fibrosis provide an environment that promotes tumor progression and invasion. We will specifically test the role of collagen fibril density, width, alignment, and crosslinking and the role of basement membrane ECM and proteases on cancer growth and invasion. All modeling will be fully integrated with experimentation to obtain realistic parameters and separately test predictions. We anticipate that this project will identify critical microenvironmental factors promoting breast cancer progression and lay the groundwork for future therapeutic intervention.
This project will combine mathematical modeling and experimental approaches to study the role of extracellular matrix on breast cancer progression and invasion. The project is relevant to human health because it will lead to a mechanistic understanding ofthe tissue and cellular factors that underlie dense breast tissue as a risk factor for invasive breast cancer and potentially identify novel therapeutic avenues.
|Oudin, Madeleine J; Jonas, Oliver; Kosciuk, Tatsiana et al. (2016) Tumor Cell-Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression. Cancer Discov 6:516-31|
|Burkel, Brian; Morris, Brett A; Ponik, Suzanne M et al. (2016) Preparation of 3D Collagen Gels and Microchannels for the Study of 3D Interactions In Vivo. J Vis Exp :|
|Esbona, Karla; Inman, David; Saha, Sandeep et al. (2016) COX-2 modulates mammary tumor progression in response to collagen density. Breast Cancer Res 18:35|
|Siqueira, Adriane S; Pinto, Monique P; Cruz, MÃ¡rio C et al. (2016) Laminin-111 peptide C16 regulates invadopodia activity of malignant cells through Î²1 integrin, Src and ERK 1/2. Oncotarget :|
|Konen, Jessica; Wilkinson, Scott; Lee, Byoungkoo et al. (2016) LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol Biol Cell 27:1069-84|
|Sung, Bong Hwan; Ketova, Tatiana; Hoshino, Daisuke et al. (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164|
|Riching, Kristin M; Keely, Patricia J (2015) Rho family GTPases: making it to the third dimension. Int J Biochem Cell Biol 59:111-5|
|Cleghorn, Whitney M; Branch, Kevin M; Kook, Seunghyi et al. (2015) Arrestins regulate cell spreading and motility via focal adhesion dynamics. Mol Biol Cell 26:622-35|
|Lee, Byoungkoo; Zhou, Xin; Riching, Kristin et al. (2014) A three-dimensional computational model of collagen network mechanics. PLoS One 9:e111896|
|Riching, Kristin M; Cox, Benjamin L; Salick, Max R et al. (2014) 3D collagen alignment limits protrusions to enhance breast cancer cell persistence. Biophys J 107:2546-58|
Showing the most recent 10 out of 12 publications